Lies, Damned Lies, and Anaphylaxis

AUTHORS:
Chioma M. Enweasor, MD¹ • Samuel Louie, MD²

AFFILIATIONS:
¹Loma Linda University, California
²University of California, Davis, California

CITATION:
Enweasor CM, Louie S. Lies, damned lies, and anaphylaxis. Consultant. 2021;61(9):e19-e24. doi:10.25270/con.2021.08.00004

DISCLOSURES:
Dr Louie reports serving as a speaker and consultant for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Regeneron, and Sanofi Genzyme. Dr Enweasor has no financial disclosures.

CORRESPONDENCE:
Samuel Louie, MD, UC Davis Medical Center, 4150 V Street, Ste 3400, Sacramento, CA 95817 (sylouie@ucdavis.edu)

Anaphylaxis is a clinical syndrome, not a single disorder. With the frequent introduction of new therapeutics such as monoclonal antibodies, vaccines such as COVID-19 vaccines, and chemotherapies, it is important to understand the underlying causes of anaphylaxis. Every clinician should be knowledgeable about diagnosing and treating patients who present with a suspected anaphylaxis reaction, especially when the point of care is away from the home or a medical facility where immediate care can be accessed. Patients and their families must be educated and better prepared to use an epinephrine autoinjector once anaphylaxis is suspected at home or away from health care facilities.

To read the sidebar on mRNA vaccines and anaphylaxis, click here.

BACKGROUND

François Magendie was the first to describe anaphylaxis reactions in 1839.¹ His experiment included injecting rabbits with egg albumin. The rabbits tolerated the first injection but died soon after the second or third. Due to the advent of sudden death, he presumed that injected albumin was poisonous to rabbits.¹

Paul Portier and Charles Richet described “aphylaxis” in 1902 when they injected 8 dogs with venom from a sea anemone to artificially induce immunity.² Several weeks later, the dogs were injected with a smaller dose of anemone venom, at which time, several of the dogs had unexpectedly collapsed and died a few minutes later.² Richet received the Nobel Prize in Medicine in 1913 for this discovery. He had explained that the Greek word “phylaxis” means “protection,” whereas “aphylaxis” or “anaphylaxis” means “no protection.”²

Now, the World Allergy Organization defines anaphylaxis as a severe, life-threatening systemic hypersensitivity reaction characterized by being rapid (minutes or a few hours after exposure to a trigger) in onset with potentially life-threatening airway, breathing, or circulatory complications and is usually—although not always—associated with skin and mucosal changes.^3,4

A terrible pitfall for any clinician and/or patient at risk is to be unprepared when anaphylaxis occurs.  However, not all causes of anaphylaxis are immunoglobulin E (IgE)-mediated hypersensitivity reactions. The textbook anaphylaxis vignette occurs after a patient has confirmed exposure to a known allergen with rapid development of pruritis, facial angioedema of the lips and tongue, urticaria, and wheezing. Allergens can include medications such as penicillin, food such as peanuts or seafood, or insect venom. 

Uncommon presentations of anaphylaxis can delay lifesaving, first-aid treatment with intramuscular epinephrine at home, outpatient clinics, and hospitals. Anaphylaxis mimicking asthma or chronic obstructive pulmonary disease exacerbations, syncope, myocardial infarction, acute abdomen pain, and septic (distributive) shock have been reported without any cutaneous signs of anaphylaxis (Table 1). 

In the authors’ experience, many patients with anaphylaxis present with 2 or more affected organ systems (eg, skin plus another body organ). The absence of a skin rash has duped many clinicians into treating anaphylaxis mimics with albuterol and systemic corticosteroids instead of epinephrine. A thorough search for a skin rash during the physical examination in such patients may be the key to diagnosing anaphylaxis. 

DIAGNOSIS

The clinical diagnosis of anaphylaxis requires a quick phenotype evaluation or pattern recognition. Most cases are, or appear, mild at first, but it is an axiom that any case of anaphylaxis can become life-threatening within 5 to 30 minutes and can last for several days.

The World Allergy Organization defines an anaphylaxis diagnosis is highly likely when any one of the following criteria are present:⁴

1. Acute onset of an illness with simultaneous involvement of the skin, mucosal tissue, or both and at least one of the following:
   1. Respiratory compromise,
   2. Reduced blood pressure or associated symptoms of end-organ dysfunction, or
   3. Severe gastrointestinal symptoms especially after exposure to nonfood allergens.
2. Acute onset of hypotension or bronchospasm or laryngeal involvement after exposure to a known or highly probably allergen for that patient, even in the absence of typical skin involvement.

In comparison, the most recent American Academy of Allergy, Asthma, and Immunology (AAAAI) practice parameter suggests an anaphylaxis diagnosis must fulfill only 1 of the following criteria:⁵ 

1. Sudden onset of illness with skin/mucosa involvement, and at least 1 of the following: sudden respiratory symptoms such as wheezing, cough, or sudden reduced blood pressure or symptoms of end-organ dysfunction such as loss of consciousness, hypotension, or incontinence. 
2. Two or more of the following symptoms after exposure to a known trigger: Sudden skin/mucosal involvement; sudden respiratory symptoms including shortness of breath, wheezing, stridor, sudden reduced blood pressure; sudden gastrointestinal symptoms including diarrhea, abdominal pain, or vomiting.
3. Reduced blood pressure after exposure to a known allergen.

These symptoms are often mistaken with other clinical presentations such as asthma exacerbations, food poisoning, or sepsis. Pruritus, a new skin rash, urticaria, angioedema, or abdominal pain are very unlikely in asthma or chronic obstructive pulmonary disease exacerbations, syncope, myocardial infarction, or septic shock.

It is a pitfall to dismiss anaphylaxis in the differential diagnosis of uncontrolled severe asthma in the absence of more generalized hypersensitivity syndrome.⁴ Another common pitfall is to think the absence of skin signs and symptoms eliminates an anaphylaxis diagnosis, but urticaria and rash are not always present and can be absent in approximately 16% of cases.⁶

Determining a Phenotype and Endotype

As with asthma, understanding the immunology of anaphylaxis can help categorize the clinical phenotype and the matching mechanism(s) or endotype(s) by which anaphylaxis phenotypes manifest from the sudden release of mediators.^1,7

Four anaphylaxis endotypes are proposed by Castells (Table 2).⁷ The first is the typical type I hypersensitivity reactions that can be IgE and/or non-IgE mediated. Patients present with flushing, pruritis, angioedema, acute respiratory distress (stridor and/or wheezing), nausea and vomiting, and/or hypotension (defining anaphylactic shock). These symptoms are seen upon re-exposure to environmental allergens, medications, or insect stings or bites.⁷

The second anaphylaxis endotype involves activated T cells, macrophages, and monocytes causing a cytokine storm, with a similar clinical presentation that is seen upon first exposure to chemotherapy and monoclonal antibodies, for example.⁷

The third anaphylaxis endotype is a mix of the first 2 pathways and involves T cells, macrophages, basophils, and mast cells and leads to a combination of clinical symptoms that include fevers, chills, pain, flushing, rash, respiratory distress, gastrointestinal symptoms, and cardiovascular collapse.⁷

The fourth anaphylaxis endotype is complement-driven, with C5a and C4a triggering mast cells and basophils to degranulate. This pathway is often triggered by contrast dyes and dialysis membranes and leads to hypotension and desaturation.⁷

An IgG FcγR neutrophil-dependent pathway has been recently reported.⁸ Patients with severe allergic reactions during neuromuscular-blockage induction had increased levels of activated neutrophils, elastase, and neutrophil extracellular traps are specific signs of neutrophil activation.⁸

This IgG-dependent pathway of anaphylaxis may lead to neutrophil degranulation similar to that of IgE-dependent degranulation of mast cells and basophils. Both pathways have histamine and platelet-activating factor in common. However, in approximately 20% of cases, no trigger is ever identified.⁹

Diagnostic Tests

No laboratory test is available at the point of care to diagnose anaphylaxis. Current diagnostic testing is still based on mast cell biomarkers—histamine and tryptase—in the serum from the blood test. The measurement of serum tryptase after allergic reactions remains underused, even after life-threatening episodes of anaphylaxis.

 Tryptase is released from mature mast cells and basophils, and levels of tryptase increase after a triggered reaction resolves, usually within 24 to 48 hours with a peak noted within 1 to 2 hours of the preceding incident.⁷ Elevated serum tryptase is a marker of mast cell degranulation and can occur in IgE- or non-IgE-mediated reactions. Levels are detected in the serum within minutes of the inciting event but will decline by 6 to 24 hours after peak.

The positive predictive value of tryptase is 93%, but the negative predictive value is only 17%, making it less than ideal for all situations.⁵ The cutoff for elevated serum tryptase is a value greater than 11.4 ng/mL or, for those with tryptase levels measured previously, 2 ng/mL plus 1.2 times the baseline.⁷ It is important to note that tryptase values are often low in patients with food-related anaphylactic reactions, which has been attributed to lower tryptase levels in mucosal mast cells vs perivascular mast cells.⁷

Serum histamine assays are another commercially available diagnostic tool, but its half-life is less than 15 minutes and, therefore, is not quite as clinically useful as serum tryptase. Other testing involves prolonged 24-hour urine collection evaluating for n-methylhistamine—a more stable form of histamine—prostaglandin D2, and leukotrienes. 

These markers are only useful for IgE-mediated reactions. Other inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and IL-1β have also been found to be increased in patients with cytokine storm-like reactions. However, little is known about their sensitivity and specificity. 

Skin testing can be helpful to parse out possible etiologies of anaphylaxis. However, skin testing needs to be done 2 to 4 weeks after the inciting event.⁷ It should be noted that patients with cytokine storm may have negative test results, and there are many drugs that can lead to clinical symptoms of hypersensitivity but cannot be tested. 

In addition, for patients presenting with potential anaphylaxis, especially in the setting of hymenoptera stings, consider testing for mastocytosis as well. It is a clonal disorder that is associated with KIT mutation D816V and is often a missed diagnosis.⁷ It is important to keep this in the differential diagnosis because these patients are at risk for cardiovascular crisis and death from severe anaphylaxis after hymenoptera stings. 

TREATMENT

It does not matter if the cause of anaphylaxis is allergic or nonallergic or if the presentation is mild, moderate, or severe; the treatment is identical. Epinephrine given intramuscularly is the first-line, first-aid treatment for anaphylaxis—not albuterol, diphenhydramine, hydrocortisone, or methylprednisolone. If you think you should give epinephrine, give it immediately and every 5 to 10 minutes until a favorable response is achieved (eg, improvement in vital signs, SpO₂, swelling, wheezing, stridor). Prompt treatment of anaphylaxis with epinephrine is associated with reduced hospitalization, morbidity, and mortality.

There are no absolute contraindications to administering epinephrine for someone with anaphylaxis. Never withhold epinephrine because of a patient’s cardiovascular history or cardiovascular disease risk factors. Delay in treatment is linked to fatal anaphylaxis (Table 3). Even after successful resuscitation, patients may die hours to days later from cerebral hypoxia.¹⁰

Therefore, you should immediately treat anaphylaxis with epinephrine whenever signs and symptoms of a generalized cutaneous, potentially allergic reaction by physical examination (ie, urticaria, angioedema, pruritus, or flushing) is accompanied by:

• Airway upper airway obstruction (eg, tongue edema) or pharyngeal or laryngeal obstruction (eg, stridor or drooling of saliva)
• Severe wheezing from bronchospasm
• Hypotension (eg, less than 90/60 mm Hg or low blood pressure that is much lower than normal for a patient with end-organ consequences)
• Syncope or near-syncope 

The therapeutic effects of epinephrine are not completely known, but epinephrine is a potent vasoconstrictor, ionotrope, and vasopressor and may stabilize mast cells and basophils by raising cAMP levels to inhibit further mediator release.⁵

Use the mnemonic device “ABC” (airway, breathing, circulation; opposite of cardiac arrest algorithm) to remember the goals of treatment and resuscitation. Another helpful mnemonic device is “E-B-FOR-BCG” (Table 4) for point-of-care treatment, which emphasizes the first-aid role of epinephrine and de-emphasizes the role of antihistamines and corticosteroids.

Epinephrine should be given intramuscularly by a prefilled syringe or autoinjector at a dose of 0.01 mg/kg of a 1:1000 solution with a maximum of 0.5 mg in adults and 0.3 mg in children into the outer mid-thigh or anterolateral aspect of the thigh.⁵ This intramuscular dose is a low-dose, first-aid treatment. Overdose is extremely unlikely with epinephrine intramuscular autoinjectors and more likely with intravenous epinephrine.¹¹

Do not use corticosteroids or antihistamines for first-aid treatment. Systemic corticosteroids and antihistamines can be added as adjunctive therapy, but they should never be considered first.⁵ Given their slow onset of action compared with the rapid deterioration often seen in patients with anaphylaxis, these medications are not helpful in the immediate management of anaphylaxis and often delay first-line treatment with epinephrine.⁵

Patients taking β blockers may not respond to epinephrine and can be given glucagon, 1 to 5 mg intravenously over 5 minutes, followed by infusion of 5 to 15 mcg/min.⁵ Rapid administration of glucagon can cause vomiting. Recommended treatment for β-blocked anaphylaxis is dopamine or isoproterenol, atropine, and/or glucagon, which increases cAMP independent of β2 receptors.⁵

 MANAGING PATIENTS AFTER AN ANAPHYLAXIS EPISODE

Anaphylaxis must remain a clinical diagnosis at the point-of-care. However, anaphylaxis is very often misdiagnosed and undertreated by patients, clinicians, schools, clinics, and hospitals. A wide variety of triggers including hymenoptera stings, medications, latex, vaccines, preservatives, monoclonal antibody biologics, and foods (ie, peanuts, tree nuts, milk) are frequently implicated, but in approximately 20% of cases no trigger is ever identified.⁹

Employ the “SAFE” system to introduce the 4 basic actions to address with patients prior to discharge from the clinic or emergency department:¹²

• Seek support
• Allergen identification and avoidance
• Follow-up for specialty care with an allergist
• Epinephrine for emergencies with a written anaphylaxis action plan

There are several versions of the written anaphylaxis action plan available to empower patients, clinicians, teachers, relatives, friends, and caregivers with the tools they need to act in the event of anaphylaxis.^13,14 Criteria for recognizing anaphylaxis is outlined in the action plan and individualized to the patient’s needs. All patients with known allergic reactions and history of anaphylaxis should create an action plan.

References

1. Jimenez-Rodriguez TW, Garcia-Neuer M, Alenazy LA, Castells M. Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers. J Asthma Allergy. 2018;11:121-142. https://doi.org/10.2147/jaa.s159411

2.  Cohen SG, Zelaya-Quesada M. Portier, Richet, and the discovery of anaphylaxis: a centennial. J Allergy Clin Immunol. 2002;110(2):331-336. https://doi.org/10.1067/mai.2002.126565

3. Simons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13-37. https://doi.org/10.1097/wox.0b013e318211496c

4. Cardona V, Ansotegui IJ, Ebisawa M, et al. World Allergy Organization anaphylaxis guidance 2020. World Allergy Organ J. 2020;13(10):100472. https://doi.org/10.1016/j.waojou.2020.100472

5. Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol. 2020;145(4):1082-1123. https://doi.org/10.1016/j.jaci.2020.01.017

6. Muraro A, Roberts G, Worm M, et al; EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026-1045. https://doi.org/10.1111/all.12437

7. Castells M. Diagnosis and management of anaphylaxis in precision medicine. J Allergy Clin Immunol. 2017;140(2):321-333. https://doi.org/10.1016/j.jaci.2017.06.012

8. Jönsson F, de Chaisemartin L, Granger V, et al. An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis. Sci Transl Med. 2019;11(500):eaat1479. https://doi.org/10.1126/scitranslmed.aat1479

9. Anagnostou K, Turner PJ. Myths, facts and controversies in the diagnosis and management of anaphylaxis. Arch Dis Child. 2019;104(1):83-90. https://doi.org/10.1136/archdischild-2018-314867

10. Simons FE. Anaphylaxis. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S161-S181. https://doi.org/10.1016/j.jaci.2009.12.981

11. Campbell RL, Bellolio MF, Knutson BD, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2015;3(1):76-80. https://doi.org/10.1016/j.jaip.2014.06.007

12. Lieberman P, Decker W, Camargo CA Jr, Oconnor R, Oppenheimer J, Simons FE. SAFE: a multidisciplinary approach to anaphylaxis education in the emergency department. Ann Allergy Asthma Immunol. 2007;98(6):519-523. https://doi.org/10.1016/s1081-1206(10)60729-6

13. Anaphylaxis Emergency Plan. American Academy of Pediatrics. Accessed July 30, 2021. https://www.healthychildren.org/SiteCollectionDocuments/AAP_Allergy_and_Anaphylaxis_Emergency_Plan.pdf

14. Anaphylaxis Emergency Action Plan. American Academy of Allergy, Asthma & Immunology. Published April 2017. Accessed July 27, 2021. https://www.aaaai.org/aaaai/media/medialibrary/pdf%20documents/libraries/anaphylaxis-emergency-action-plan.pdf